Abstract MM is characterized by widespread disease at diagnosis with the presence of multiple lytic lesions and disseminated involvement of the bone marrow (BM), implying that the progression of MM involves a continuous circulation of the MM cells in the peripheral blood and re-entrance into the BM. Chemokines play a central role in lymphocyte trafficking and homing, specifically the chemokine SDF-1, and its receptors, CXCR4 along with the recently identified receptor CXCR7. We hypothesize that modulation of the capacity of MM cells to reside in their microenvironment will change their biologic properties and induce sensitivity to apoptosis. Specific Aim 1: To identify mechanisms of homing of MM cells in response to the SDF-1/CXCR4 axis. We will test this aim by determining the long-term biological sequelae of inhibition of SDF-1-dependent homing of MM and its effect on tumor progression, determining the differences in kinetics of homing between MM cells and other BM microenvironment cells, identifying the downstream signaling pathways that regulate MM cells' homing in response to CXCR4 and CXCR7 in vitro and in vivo, and difference in signaling of these two receptors in MM, and identifying the role of other chemokine receptors and adhesion molecules in the regulation of homing. Specific Aim 2: To determine the in vitro and in vivo effects of the SDF-1/CXCR4 axis on adhesion and survival of MM cells by identifying the biological changes that occur in MM cells adherent to the BM microenvironment compared to those in the peripheral blood, identifying the interaction of SDF-1/CXCR4 with adhesion molecules namely VLA-4 and LFA-1, and identifying the effect of inhibition of CXCR4/CXCR7 and/or adhesion molecules on growth and survival of MM cells in vivo. Specific Aim 3: To identify mechanisms of egression/mobilization of MM cells in response to CXCR4/CXCR7 inhibition by determining the biological sequelae of mobilization of MM cells in response to inhibition of CXCR4, CXCR7, VLA-4 and MMP2/9 inhibitors, determining the difference in kinetics of mobilization of MM cells compared to other bone marrow cells, and determining whether MM cells mobilized out of the BM will be more sensitive to apoptosis by cytotoxic agents compared to malignant cells residing in the BM. Targeting trafficking will lead to a paradigm shift in therapeutic approaches in MM, where we will alter the capacity of MM cells to reside in their protective bone marrow microenvironment by inducing egression and preventing homing and adhesion, leading to increased sensitivity to apoptosis. Relevance to Public Health: The mechanisms of tumor progression in myeloma are not well understood. We will study the role of the chemokine SDF-1 and its receptors in the regulation of entry of myeloma cells into the bone marrow, their adhesion and their exit into the circulation. Targeting this process by mobilizing myeloma cells out of the marrow will lead to a higher sensitivity to killing of the cells with cytotoxic agents.